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1.  Correction: Disruption of Protein Kinase A in Mice Enhances Healthy Aging 
PLoS ONE  2010;5(2):10.1371/annotation/c7cad2dc-1eca-487e-89ae-151a22d8a0b4.
doi:10.1371/annotation/c7cad2dc-1eca-487e-89ae-151a22d8a0b4
PMCID: PMC2820562
3.  Mitochondrial oxidative stress mediates induction of autophagy and hypertrophy in angiotensin-II treated mouse hearts 
Autophagy  2011;7(8):917-918.
Autophagy is characterized by recycling of cellular organelles and can be induced by several stimuli, including nutrient deprivation and oxidative stress. As a major site of free radical production during oxidative phosphorylation, mitochondria are believed to be primary targets of oxidative damage during stress. Our recent study demonstrated that angiotensin II increases cardiac mitochondrial reactive oxygen species (ROS) production, causes a decline of mitochondrial membrane potential in cardiomyocytes and increases cardiac mitochondrial protein oxidative damage and mitochondrial DNA deletions. The deleterious effects of angiotensin II on mitochondria are associated with an increase in autophagosomes and increased signaling of mitochondrial biogenesis, interpreted as an attempt to replenish the damaged mitochondria and restore energy production. Direct evidence for the central role of mitochondrial ROS was investigated by comparing the effect on mice overexpressing catalase targeted to mitochondria (mCAT) and mice overexpressing peroxisomal targeted catalase (pCAT, the natural site of catalase) challenged by angiotensin II or Gαq overexpression. The mCAT, but not pCAT, mice are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage, biogenesis and autophagy induced by angiotensin II, as well as heart failure induced by overexpression of Gαq.
doi:10.4161/auto.7.8.15813
PMCID: PMC3359471  PMID: 21505274
mitochondria; autophagy; reactive oxygen species; catalase; angiotensin II; heart failure
4.  Correction: Disruption of Protein Kinase A in Mice Enhances Healthy Aging 
PLoS ONE  2010;5(2):10.1371/annotation/d51a16b6-dc82-4cdb-8118-d7c982233d7c.
doi:10.1371/annotation/d51a16b6-dc82-4cdb-8118-d7c982233d7c
PMCID: PMC2820560
5.  Global Proteomics and Pathway Analysis of Pressure-overload Induced Heart Failure and Its Attenuation by Mitochondrial Targeted Peptides 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.113.000406.
Background
We investigated the protective effects of mitochondrial-targeted antioxidant and protective peptides, SS31 and SS20, on cardiac function, proteomic remodeling and signaling pathways.
Methods and Results
We applied an improved label-free shotgun proteomics approach to evaluate the global proteomics changes in transverse aortic constriction (TAC) induced heart failure, and the associated signaling pathway changes using Ingenuity Pathway Analysis (IPA). We found 538 proteins significantly changed after TAC, which mapped to 53 pathways. The top pathways were in the categories of actin cytoskeleton, mitochondrial function, intermediate metabolism, glycolysis / gluconeogenesis and citrate cycle. Concomitant treatment with SS31 ameliorated the congestive heart failure phenotypes and mitochondrial damage induced by TAC, in parallel with global attenuation of mitochondrial proteome changes, with an average of 84% protection of mitochondrial and 69% of non-mitochondrial protein changes. This included significant amelioration of All the IPA pathways noted above. SS20 had only modest effects on heart failure and this tracked with only partial attenuation of global proteomics changes; furthermore, while actin cytoskeleton pathways were significantly protected in SS20, mitochondrial and metabolic pathways essentially were not.
Conclusions
This study elucidates the signaling pathways significantly changed in pressure-overload induced heart failure. The global attenuation of TAC-induced proteomic alterations by the mitochondrial targeted peptide SS-31 suggests that perturbed mitochondrial function may be an upstream signal to many of pathway alterations in TAC and supports the potential clinical application of mitochondrial-targeted peptide drugs for the treatment heart failure.
doi:10.1161/CIRCHEARTFAILURE.113.000406
PMCID: PMC3856238  PMID: 23935006
heart failure; mitochondria; proteomics; signal transduction
6.  Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart 
Aging Cell  2014;13(3):529-539.
Chronic caloric restriction (CR) and rapamycin inhibit the mechanistic target of rapamycin (mTOR) signaling, thereby regulating metabolism and suppressing protein synthesis. Caloric restriction or rapamycin extends murine lifespan and ameliorates many aging-associated disorders; however, the beneficial effects of shorter treatment on cardiac aging are not as well understood. Using a recently developed deuterated-leucine labeling method, we investigated the effect of short-term (10 weeks) CR or rapamycin on the proteomics turnover and remodeling of the aging mouse heart. Functionally, we observed that short-term CR and rapamycin both reversed the pre-existing age-dependent cardiac hypertrophy and diastolic dysfunction. There was no significant change in the cardiac global proteome (823 proteins) turnover with age, with a median half-life 9.1 days in the 5-month-old hearts and 8.8 days in the 27-month-old hearts. However, proteome half-lives of old hearts significantly increased after short-term CR (30%) or rapamycin (12%). This was accompanied by attenuation of age-dependent protein oxidative damage and ubiquitination. Quantitative proteomics and pathway analysis revealed an age-dependent decreased abundance of proteins involved in mitochondrial function, electron transport chain, citric acid cycle, and fatty acid metabolism as well as increased abundance of proteins involved in glycolysis and oxidative stress response. This age-dependent cardiac proteome remodeling was significantly reversed by short-term CR or rapamycin, demonstrating a concordance with the beneficial effect on cardiac physiology. The metabolic shift induced by rapamycin was confirmed by metabolomic analysis.
doi:10.1111/acel.12203
PMCID: PMC4040127  PMID: 24612461
caloric restriction; cardiac aging; dynamics; proteomics; rapamycin
7.  Mitochondrial oxidative stress in aging and healthspan 
The free radical theory of aging proposes that reactive oxygen species (ROS)-induced accumulation of damage to cellular macromolecules is a primary driving force of aging and a major determinant of lifespan. Although this theory is one of the most popular explanations for the cause of aging, several experimental rodent models of antioxidant manipulation have failed to affect lifespan. Moreover, antioxidant supplementation clinical trials have been largely disappointing. The mitochondrial theory of aging specifies more particularly that mitochondria are both the primary sources of ROS and the primary targets of ROS damage. In addition to effects on lifespan and aging, mitochondrial ROS have been shown to play a central role in healthspan of many vital organ systems. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and dysfunction in aging and healthspan, including cardiac aging, age-dependent cardiovascular diseases, skeletal muscle aging, neurodegenerative diseases, insulin resistance and diabetes as well as age-related cancers. The crosstalk of mitochondrial ROS, redox, and other cellular signaling is briefly presented. Potential therapeutic strategies to improve mitochondrial function in aging and healthspan are reviewed, with a focus on mitochondrial protective drugs, such as the mitochondrial antioxidants MitoQ, SkQ1, and the mitochondrial protective peptide SS-31.
doi:10.1186/2046-2395-3-6
PMCID: PMC4013820  PMID: 24860647
Mitochondria; Oxidative stress; Aging; Healthspan
8.  Mitochondria and Cardiovascular Aging 
Circulation research  2012;110(8):10.1161/CIRCRESAHA.111.246140.
Old age is a major risk factor for cardiovascular diseases. Several lines of evidence in experimental animal models have indicated the central role of mitochondria both in lifespan determination and cardiovascular aging. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and biogenesis as well as the crosstalk between mitochondria and cellular signaling in cardiac and vascular aging. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging include endothelial dysfunction, reduced vascular elasticity and chronic vascular inflammation. Both cardiac and vascular aging involve neurohormonal signaling (e.g. renin-angiotensin, adrenergic, insulin-IGF1 signaling) and cell-autonomous mechanisms. The potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants, calorie restriction, calorie restriction mimetics and exercise training.
doi:10.1161/CIRCRESAHA.111.246140
PMCID: PMC3867977  PMID: 22499901
9.  Mitochondrial oxidative stress mediates Angiotensin II-induced cardiac hypertrophy and Gαq overexpression-induced heart failure 
Circulation research  2011;108(7):837-846.
Rationale
Mitochondrial dysfunction has been implicated in several cardiovascular diseases; however, the roles of mitochondrial oxidative stress and DNA damage in hypertensive cardiomyopathy are not well understood.
Objective
We evaluated the contribution of mitochondrial reactive oxygen species (ROS) to cardiac hypertrophy and failure by using genetic mouse models overexpressing catalase targeted to mitochondria and to peroxisomes.
Methods and Results
Angiotensin II increases mitochondrial ROS in cardiomyocytes, concomitant with increased mitochondrial protein carbonyls, mitochondrial DNA deletions, increased autophagy and signaling for mitochondrial biogenesis in hearts of Angiotensin II treated mice. The causal role of mitochondrial ROS in Angiotensin II-induced cardiomyopathy is shown by the observation that mice that overexpress catalase targeted to mitochondria, but not mice that overexpress wild-type peroxisomal catalase, are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage induced by Angiotensin II, as well as heart failure induced by overexpression of Gαq. Furthermore, primary damage to mitochondrial DNA, induced by zidovudine administration or homozygous mutation of mitochondrial polymerase gamma, is also shown to contribute directly to the development of cardiac hypertrophy, fibrosis and failure.
Conclusions
These data indicate the critical role of mitochondrial ROS in cardiac hypertrophy and failure and support the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy.
doi:10.1161/CIRCRESAHA.110.232306
PMCID: PMC3785241  PMID: 21311045
mitochondria; reactive oxygen species; angiotensin; cardiomyopathy; heart failure
10.  Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy 
Objectives
We investigated the effect of reducing mitochondrial oxidative stress by the mitochondrial-targeted antioxidant peptide SS-31 in hypertensive cardiomyopathy.
Background
Oxidative stress has been implicated in hypertensive cardiovascular diseases. Mitochondria and NADPH oxidase have been proposed as primary sites of reactive oxygen species (ROS) generation.
Methods
The mitochondrial targeted antioxidant peptide SS-31 was used to determine the role of mitochondrial oxidative stress in Angiotensin II (Ang)-induced cardiomyopathy, as well as in Gαq overexpressing mice with heart failure.
Results
Angiotensin II induces mitochondrial ROS in neonatal cardiomyocytes, which is prevented by SS-31, but not the non-targeted antioxidant N-acetyl cysteine (NAC). Continuous administration of Ang for 4 weeks in mice significantly increased both systolic and diastolic blood pressure, and this was not affected by SS-31 treatment. Ang was associated with upregulation of NADPH oxidase 4 (NOX4) expression, increased cardiac mitochondrial protein oxidative damage and induced the signaling for mitochondrial biogenesis. Reducing mitochondrial ROS by SS-31 substantially attenuated Ang-induced NOX4 upregulation, mitochondrial oxidative damage, upregulation of mitochondrial biogenesis, phosphorylation of p38 MAP kinase, and prevented apoptosis, concomitant with amelioration of Ang induced cardiac hypertrophy, diastolic dysfunction, and fibrosis, despite the absence of blood pressure lowering effect. NAC did not show any beneficial effect. SS-31 administration for 4 weeks also partially rescued the heart failure phenotype of Gαq overexpressing mice.
Conclusions
Mitochondrial targeted peptide SS-31 ameliorates cardiomyopathy resulting from prolonged Ang stimulation as well as Gαq overexpression, suggesting its potential clinical application for target organ protection in hypertensive cardiovascular diseases.
doi:10.1016/j.jacc.2010.12.044
PMCID: PMC3742010  PMID: 21620606
mitochondria; hypertension; cardiomyopathy
11.  Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease 
Antioxidants & Redox Signaling  2012;16(12):1492-1526.
Abstract
Cardiovascular diseases (CVDs) are the major causes of death in the western world. The incidence of cardiovascular disease as well as the rate of cardiovascular mortality and morbidity increase exponentially in the elderly population, suggesting that age per se is a major risk factor of CVDs. The physiologic changes of human cardiac aging mainly include left ventricular hypertrophy, diastolic dysfunction, valvular degeneration, increased cardiac fibrosis, increased prevalence of atrial fibrillation, and decreased maximal exercise capacity. Many of these changes are closely recapitulated in animal models commonly used in an aging study, including rodents, flies, and monkeys. The application of genetically modified aged mice has provided direct evidence of several critical molecular mechanisms involved in cardiac aging, such as mitochondrial oxidative stress, insulin/insulin-like growth factor/PI3K pathway, adrenergic and renin angiotensin II signaling, and nutrient signaling pathways. This article also reviews the central role of mitochondrial oxidative stress in CVDs and the plausible mechanisms underlying the progression toward heart failure in the susceptible aging hearts. Finally, the understanding of the molecular mechanisms of cardiac aging may support the potential clinical application of several “anti-aging” strategies that treat CVDs and improve healthy cardiac aging.
I. Introduction
II. Aging and Epidemiology of CVDs
III. Physiology of Cardiac Aging
A. Ventricular changes
B. Valvular changes
IV. Animal Models of Cardiac Aging
A. Rodents
B. Drosophila
C. Canines
D. Nonhuman primates
V. Mitochondria and the Free Radical Theory of Aging
A. ROS and aging
B. Pleiotropy of ROS
C. Mitochondrial hormesis in aging
D. Mitochondrial turnover in aging
VI. Molecular Mechanisms of Cardiac Aging
A. Mitochondrial oxidative stress in cardiac aging
B. Neurohormonal regulation of cardiac aging
1. Renin-angiotensin system in cardiac aging
2. B-adrenergic signaling
3. Insulin/insulin-like growth factor 1/PI3K signaling
4. Natriuretic peptides signaling
C. Nutrient signaling in cardiac aging
D. Cardiac stem cell aging and telomeres
VII. Aging, Oxidative Stress, and CVDs
A. Oxidative stress and mitochondria in CVDs
1. The central role of mitochondrial oxidative stress and redox status in hypertension and heart failure
2. The role of mitochondria and oxidative stress in IR injury
B. Mechanisms of progression to heart failure in the aged hypertrophic heart
1. Increased cardiomyocyte death
2. ECM remodeling
3. Alteration of calcium handling proteins
4. Hypoxic response and angiogenesis
5. Mitochondrial dysfunction and abnormalities in energetics
VIII. Exercise, Cardiovascular Risks, and Cardiac Aging
IX. Emerging “Anti-Aging” Interventional Strategies for Cardiac Aging and CVDs
A. Dietary restriction
B. Antioxidant interventions
1. Nontargeted antioxidants
2. Mitochondrial-targeted antioxidants
a. TPP+conjugated antioxidants
b. Szeto-schiller peptides
C. Resveratrol and SIRTs activators
X. Conclusion and Future Directions
doi:10.1089/ars.2011.4179
PMCID: PMC3329953  PMID: 22229339
12.  Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival 
Science translational medicine  2012;4(144):144ra103.
Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna–/– mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna–/– mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors.
doi:10.1126/scitranslmed.3003802
PMCID: PMC3613228  PMID: 22837538
13.  Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress 
Cardiovascular Research  2011;93(1):79-88.
Aims
We investigate the role of mitochondrial oxidative stress in mitochondrial proteome remodelling using mouse models of heart failure induced by pressure overload.
Methods and results
We demonstrate that mice overexpressing catalase targeted to mitochondria (mCAT) attenuate pressure overload-induced heart failure. An improved method of label-free unbiased analysis of the mitochondrial proteome was applied to the mouse model of heart failure induced by transverse aortic constriction (TAC). A total of 425 mitochondrial proteins were compared between wild-type and mCAT mice receiving TAC or sham surgery. The changes in the mitochondrial proteome in heart failure included decreased abundance of proteins involved in fatty acid metabolism, an increased abundance of proteins in glycolysis, apoptosis, mitochondrial unfolded protein response and proteolysis, transcription and translational control, and developmental processes as well as responses to stimuli. Overexpression of mCAT better preserved proteins involved in fatty acid metabolism and attenuated the increases in apoptotic and proteolytic enzymes. Interestingly, gene ontology analysis also showed that monosaccharide metabolic processes and protein folding/proteolysis were only overrepresented in mCAT but not in wild-type mice in response to TAC.
Conclusion
This is the first study to demonstrate that scavenging mitochondrial reactive oxygen species (ROS) by mCAT not only attenuates most of the mitochondrial proteome changes in heart failure, but also induces a subset of unique alterations. These changes represent processes that are adaptive to the increased work and metabolic requirements of pressure overload, but which are normally inhibited by overproduction of mitochondrial ROS.
doi:10.1093/cvr/cvr274
PMCID: PMC3243039  PMID: 22012956
Mitochondria; Oxidative stress; Proteome; Pressure overload; Cardiomyopathy
14.  Age-Dependent Cardiomyopathy in Mitochondrial Mutator Mice is Attenuated by Overexpression of Catalase Targeted to Mitochondria 
Aging Cell  2010;9(4):536-544.
Mitochondrial defects have been found in aging and several age-related diseases. Mice with a homozygous mutation in the exonuclease encoding domain of mitochondrial DNA polymerase gamma (Polgm/m) are prone to age-dependent accumulation of mitochondrial DNA mutations and have shown a broad spectrum of aging-like phenotypes. However, the mechanism of cardiac phenotypes in relation to the role of mitochondrial DNA mutations and oxidative stress in this mouse model has not been fully addressed. We demonstrate age-dependent cardiomyopathy in Polgm/m mice, which by 13-14 months of age displays marked cardiac hypertrophy and dilatation, impairment of systolic and diastolic function and increased cardiac fibrosis. This age-dependent cardiomyopathy is associated with increases in mitochondrial DNA (mtDNA) deletions and protein oxidative damage, increased expression of apoptotic and senescence markers, as well as a decline in signaling for mitochondrial biogenesis. The relationship of these changes to mitochondrial reactive oxygen species (ROS) was tested by crossing Polgm/m mice with mice that overexpress mitochondrial targeted catalase (mCAT). All of the above phenotypes were partially rescued in Polgm/m/mCAT mice. These data indicate that accumulation of mitochondrial DNA damage with age can lead to cardiomyopathy, and that this phenotype is partly mediated by mitochondrial oxidative stress.
doi:10.1111/j.1474-9726.2010.00581.x
PMCID: PMC3265170  PMID: 20456298
mitochondria; mutation; aging; cardiomyopathy; oxidative stress
16.  Mitochondrial oxidative stress and mammalian healthspan 
Mechanisms of ageing and development  2010;131(7-8):527-535.
Aging of the American society is leading to a growing need for disease-modifying interventions to treat age-related diseases and enhance healthspan. Mitochondria and mitochondrially-generated reactive oxygen species appear to play a central role in these processes and are a likely target for interventions. Conventional, untargeted antioxidants have not demonstrated a clear benefit in human studies. As a result, approaches have been developed to target antioxidants specifically to mitochondria. Studies have employed a wide array of targeted molecules including antioxidant enzymes such as catalase, peroxiredoxin, superoxide dismutases and small molecular compounds which recapitulate the antioxidant activities of these enzymes. Lifespan and healthspan effects differ between interventions suggesting varied roles for specific mitochondrial reactive oxygen species and their impact on usual aging. Consistent findings in myocardial protection across various interventions support a focus on the impact of cardiac aging on healthspan. The advancement of mitochondrially-targeted small molecule antioxidants suggests the prospect of swift translation to human use.
doi:10.1016/j.mad.2010.06.002
PMCID: PMC2933331  PMID: 20566356
Mitochondria; antioxidants; drug targeting; healthspan
17.  Cardiac Aging in Mice and Humans: the Role of Mitochondrial Oxidative Stress 
Trends in cardiovascular medicine  2009;19(7):213-220.
Age is a major risk factor for cardiovascular diseases, not only because it prolongs exposure to several other cardiovascular risks, but also owing to intrinsic cardiac aging, which reduces cardiac functional reserve, predisposes the heart to stress and contributes to increased cardiovascular mortality in the elderly. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans, including left ventricular hypertrophy, fibrosis and diastolic dysfunction. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations, increased mitochondrial biogenesis, as well as decreased cardiac SERCA2 protein. All of these age-related changes are significantly attenuated in mice overexpressing catalase targeted to mitochondria (mCAT). These findings demonstrate the critical role of mitochondrial reactive oxygen species (ROS) in cardiac aging and support the potential application of mitochondrial antioxidants to cardiac aging and age-related cardiovascular diseases.
doi:10.1016/j.tcm.2009.12.004
PMCID: PMC2858758  PMID: 20382344
18.  Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging 
Circulation  2009;119(21):2789-2797.
Background:
Age is a major risk for cardiovascular diseases. Although mitochondrial reactive oxygen species (ROS) have been proposed as one of the causes of aging, their role in cardiac aging remains unclear. We have previously shown that overexpression of catalase targeted to mitochondria (mCAT) prolongs murine median lifespan by 17-21%.
Methods and Results:
We used echocardiography to study cardiac function in aging cohorts of wild type (WT) and mCAT mice. Changes found in WT mice recapitulate human aging: age-dependent increases in left ventricular mass index (LVMI) and left atrial dimension, worsening of the myocardial performance index (MPI), and a decline in diastolic function. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations and deletions and mitochondrial biogenesis, increased ventricular fibrosis, enlarged myocardial fiber size, decreased cardiac SERCA2 protein and activation of the calcineurin-NFAT pathway. All of these age-related changes were significantly attenuated in mCAT mice. Analysis of survival of 130 mice demonstrated that echocardiographic cardiac aging risk scores were significant predictors of mortality. The estimated attributable risk to mortality for these two parameters was 55%.
Conclusion:
This study shows that cardiac aging in the mouse closely recapitulates human aging and demonstrates the critical role of mitochondrial ROS in cardiac aging and the impact of cardiac aging on survival. These findings also support the potential application of mitochondrial antioxidants in ROS-related cardiovascular diseases.
doi:10.1161/CIRCULATIONAHA.108.822403
PMCID: PMC2858759  PMID: 19451351
aging; diastole; mitochondria; oxidant stress; survival

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